Females are born with a finite pool of primordial follicle which, once depleted, cannot be replaced. Exposure to environmental chemicals can cause depletion of this pool, leading to premature ovarian failure, or early menopause. A variety of health disorders are associated with menopause, thus early menopause represents a genuine health risk. 4-vinylcyclohexene (VCH) and its diepoxide metabolite, VCD, cause selective destruction of primordial and small primary follicles in the ovaries of rats and mice, and serve as model chemicals to study the mechanisms by which environmental chemical exposures cause ovotoxicity. Preliminary studies have supported that alterations in the c-Kit/Kit ligand/PI3 kinase signaling pathway are involved in VCD-induced ovotoxicity. Additionally, inhibition of PI3 kinase signaling protected against VCD-induced primordial follicle loss, while estradiol treatment protected small primary follicles from VCD-induced destruction. The hypothesis to be tested is that VCD causes selective loss of ovarian small pre-antral follicles by stimulation of primordial to small primary recruitment via interactions with the PI3K signaling pathway. Four Specific Aims will be investigated in this proposal: 1) identification of the cellular event that initiates VCD-induced ovotoxicity, 2) examination of increased primordial to primary follicle recruitment during VCD-induced ovotoxicity, 3) characterization of the pathways that protect against follicle loss caused by VCD, and 4) confirmation of downstream events involved in VCD-induced follicle destruction. The results will provide much needed insight into basic ovarian physiological processes as well as elucidating perturbations to these processes that are a result of environmental chemical exposures. The ultimate aim is to fully understand and identify solutions to prevent premature ovarian failure occurring due to xenobiotic exposures in females. This greater awareness will lead to an appreciation of the global impact of the environment on age of menopause in women. PUBLIC HEALTH RELEVANCE: The major objective of the studies is to identify more precisely cellular mechanisms by which 4- vinylcyclohexene diepoxide damages ovarian follicles. The results will provide an understanding of mechanisms by which environmental chemicals may cause early menopause in women. This will lead to an appreciation of the global impact of the environment on the reproductive life span in women.